Cardioactive oxido-bufatrienolides

ABSTRACT

CARDIOACTIVE OXIDO-CARDADIENOLIDES AND OXIDO-BUFATRIENOLIDES OF THE FORMULA   3-R1,14,15-(-O-),17-R-4-GONENE   WHEREIN R IS A CARDENOLIDE OR BUFADIENOLIDE RING AND R1 IS -OH IN THE B-POSITION OR KETO. METHODS OF MAKING SUCH COMPOUNDS. AS SPECIFIC OXIDO-BUFATRIENOLIDES: 3-OXO14,15B-OXIDO-BUFA-4,20(21),22(23)-TRIENOLIDE; 3BHYDROXY-14,15B-OXIDO-BUFA-4,20(21),22(23)-TRIENOLIDE.

United States Patent 01 iice 3,639,392 Patented Feb. 1, 1972 US. Cl. 260-23957 2 Claims ABSTRACT OF THE DISCLOSURE Cardioactive oxido-cardadienolides and oxido-bufatrienolides of the formula wherein R is a cardenolide or bufadienolide ring and R is -OH in the [at-position or keto. Methods of making such compounds. As specific oxido-bufatrienolides: 3-oxo- 14,1513 oxido bufa 4,20(21),22(23) trienolide; 313- hydroxy- 14, 1 fi-oxido-bufa-4,20(2 1 ,22 (23 -trienolide.

The present invention relates to oxido-cardadienolides or oxido-bufatrienolides of the. Formula I 'means of per-acids into the corresponding 14,15oz-OXidO- compounds, these are treated with acid agents, the 1418-150:- dihydroxy-compounds that have formed are transformed with the aid of sulfochloride into the corresponding 14B- hYdIOXY-lSa-SlllfOIllC acid esters, and from the latter the sulfonic acid radical is separated.

If the corresponding 3fi-hydroxy-compounds are desired, the 3 oxo 14,15oc oxido carda 4,20(22) dienolides or 3 OX0 14,155 oxido bufa 4,20(2l),22(23)- trienolides obtained according to (a) or (b) are reduced with the aid of metal hydrides.

The separate process steps are compiled below in schematicform:

In the above formulas, R stands for the radical of a sulfonic acid.

(a) The reaction of the starting substances of Formula II with N-halogeno-amides or hypohalogenous acids according to variant (a) is carried out in a manner similar to that used for analogous cases (cf. Engel and Bach,

Steroids, volume 3, page 593), for example with N- bromo-acetamide in the presence of perchloric acid or also, advantageously, with N-bromosulfonamides of an aromatic sulfonic acid, for example N,N-di-bromo-benzene-sulfonamide in a weakly acid medium, in inert s01- vents.

The bromohydrins of the Formula III so obtained may be converted either directly in the reaction mixture or after precipitation with water, without purification, by means of weak alkali, for example a mixture of sodium acetate and glacial acetic acid in methanol having a pH- value of 7.4 or by treatment with basic or neutral or acid aluminium oxide as that used in chromatography, in a solvent which is inert towards aluminum oxide, into the 14,15fl-oxido-compounds of the Formula Ia. There may, of course, also be used other agents that split oif HBr, for example organic bases such as pyridine, triethylaminc or 4,5-diaza-bicyclo-[4,3,0]-nonene or alkalis.

(b) For converting the starting substances of Formula II into the 14,15a-oxido-compounds of Formula IV according to (b), there may be used, for example mono-. perphthalic acid, perbenzoic acid or mono-chloro-perben: zoic acid. The splitting of the epoxide compounds of the Formula IV yielding the diols of Formula V is effected with acids such as perchloric acid, sulfuric acid, hydrochloric acid or p-toluene-snlfonic acid in solvents such as dioxane, tetrahydrofurane, methanol, or acetone, with or without addition of water. For preparing the sulfonates of Formula VI from V, methane-sulfonic acid chloride or p-toluene-sulfonic acid chloride is preferably used. The separation of the sulfonic acid radical can be elfected by treatment of the snlfonates with silica gel, aluminum oxide, sodium acetate or sodium carbonate.

If desired, the oxo-compounds of the formula Ia can be reduced selectively to the corresponding hydroxy compounds of the Formula Ib. For this purpose, metal hydrides, preferably sodium boron hydride, lithium boron ci io hydride or lithium-tritert.butoxy-aluminum hydride are Br-C cu on Ha 6mm used. As the reaction medium especially ethers, for exi 1 c11 ample diethyl ether, dioxane or tetrahydrofurane, are used. c .n c -;cu The reaction time ranges from 1 to several hours, the (c n m J reaction temperature is in the range of between 20 C. :1 and the boiling temperature of the ether used.

The compound of Formula II, in which R stands for the bufa-dienolide group, can be prepared starting from CH 600C113 the known 15u-hydroxy-desoxy-corticosterone according to the process described in US. patent application Ser. (H CH0 No. 735,964, filed by K. Radscheit et al. on June 11, 1968. 15 Eli/Wake QQUL-O'L'. HCl II (r 5.111; by successive oxidation of the 21-hydroxyl group, acetal- D 1100K lidu r1112 ization of the corresponding 21-aldehyde group, tosylation of the hydroxyl group in 15a-position, formation of the The corresponding cardenolide of Formula II may be Al4-double bond by splitting off of toluene-sulfonic acid prepared according to the process described in Belgian by means of lithium carbonate, protection of the 3-keto 2 Pat. 695,311 starting from 1Sa-hydroXy-desoxy-corticosgroup by enol-ester formation with ortho-formic acid terone by reaction with a sulfochloride, substitution of ester, formation of the 20,22-epoxide with trimethyl-sulfothe sulfonic acid ester group for the malonic acid seminium iodide/NaH, simultaneous separation of the acetal ester grouping and ring closure of the latter by means of and enol-ester groups and cleavage of the epoxide ring an organic base, according to the following scheme:

(ar on fu oso u' co co R'SO Cl on I .pso n I cu 0 co 0 12 I M (:0 cu cooa' C CH CH COOiuG' 2 coon -os0 R' with HBr, restoration of the 20,22epoxide ring by treat- The products obtained according to the present invening the bromohydrine thus formed with triethylamine, setion are novel and they are distinguished by a strongly lective condensation of the 21-aldehyde group with carbopositive inotropic action and as a consequence thereof, methoxy-methyl-diethyl phosphonate to the 21-carboa strongly marked cardioactivity. They, therefore, are methoxy-methylene compound with conservation of the suitable for the medicinal treatment of heart damages, 3-keto-group, isomerization of the 20,22-epoxide ring to especially of cardiac insufiiciency and tachycardia. They the 22-aldehyde with the aid of boron-trifluoride etherare preferably administered in the form of tablets or ate and ring closure to compound H by means of aqueous drages which contain, in addition to the active substances, methanolic HCl. the usual adjuvants and excipients, for example, lactose,

The individual steps of the synthesis are shown by the starch, tragacanth, etc. following formula scheme: The products of the invention may also be used as intermediates in the manufacture of medicaments, for example by conversion of the 3-hydroxy compounds into corre- CH'OH CH0 sponding derivatives of the 3-hydroxy group known in z I steroid chemistry, for example ethers or esters. c L The following examples illustrate the invention: W CuUDAz; 1:01 EXAMPLE 1 0 %V \W 3-oxo-l4,15p-oxido-carda-4,20(22)dienolide 150M! d F BL (A) 9.28 ml. of 0.39 N-perchloric acid were intro- Cw duced, while stirring, at about 15-l8 G, into a suspension cu(ocu cu(ocH I i 2 of 5.64 g. of 3-oxo-carda-4,l4,20(22)-trienolide (melting o F1351)? c o 13 cc c o polnt 275-278 C.) 1n 57 m1. of peroxide-free dioxane. l Then, 2.54 g. of N-bromoacetamide were added likewise I l at 15-18 C., while stirring and with exclusion of light, within 30 minutes. The whole was stirred for 1 hour at 15-18 C., then for 3-5 minutes while cooling with ice mums)? and the reaction mixture was then poured, while stirring, on; into a mixture of 200 g. of ice and 200 ml. of water. The l o crude 3-oxo-14 8-hydroxy 15a bromo-carda-4,20(22)- 1Q dienolide that had precipitated was filtered otf with suction "Br and washed with water. The filter residue was dissolved in 40 ml. of methylene chloride and the solution was separated from the water still present. The organic phase was combined with 210 ml. of 95% methanol, then 10 ml. of a buffer mixture of 139 g. of sodium acetate (containing 3 mols of crystal water), 690 ml. of methanol and 25 ml. of glacial acetic acid were added. The pH-value was maintained at 7 by occasional addition of buffer solution of the above composition. After 3 hours, the solution was concentrated to a small volume in a rotary evaporator. The residue was dissolved in a mixture of methylene chloride and ether, washed with water and, after drying with sodium sulfate, was evaporated to dryness under reduced pressure. After recrystallization'of the crude product from a mixture of methylene chloride and methanol, 3.42 g. of 3-oxo-14,15B-oxido-carda-4,20(22)- dienolide melting at 208-212 C. were obtained.

(B) 6.36 ml. of glacial acetic acid and immediately thereafter 7.82 g. of N,N-dibromo-benzenesulfonamide were added at +2 C., while stirring and with exclusion of light, to a suspension of 9 g. of 3-oxo-carda-4,14,20- (22)-trienolide in 300 ml. of peroxide-free dioxane and 54 ml. of water. Then, the whole was stirred for 1 hour under the same conditions. The reaction mixture was poured into a solution of 50 ml. of saturated sodium thiosulfate solution in 1.4 l. of ice-cold water and extracted three times by shaking with 150 ml. portions of methylene chloride. The extracts were washed three times with ice-cold water, dried over sodium sulfate and concentrated under reduced pressure to about 120 ml. at as low a bath temperature as possible (about 30-40 C.). After addition of 320 ml. of methanol and 8 ml. of water, 66 ml. of the above buffer solution and 20 ml. of a saturated aqueous sodium acetate solution were added. The whole was stirred for 3 hours and worked up as described above. After recrystallization from a mixture of methylene chloride and methanol, 5.96 g. of 3-oxo-14,155-oxido-carda- 4,20(22)-dienolide melting at 208-212" C. were obtained.

EXAMPLE 2 3 ,6-hydroxy-14,15 ,8-oxido-carda-4,20(22) -dienolide 77 ml. of a solution of lithium-aluminum-tri-tert.- butoxyhydride in tetrahydrofurane (containing 145 mg. per ml., determined by iodometric titration) were added within 15 minutes while stirring, to a solution of 1.5 g. of 3-oxo-14,15B-oxido-carda 4,20(22) dienolide in 150 ml. of absolute tetrahydrofurane that had been cooled to 5' C. The whole was then stirred for 2 hours and 40 minutes While cooling with ice and, while continuing stirring and cooling, a mixture of 58 ml. of water and 3.51 ml. of glacial acetic acid was added dropwise. The whole was heated to room temperati'lre and stirred for 45 minutes. The reaction mixture was combined with an equal volume of water and filtered with suction through a clarifying filter. The filter residue was well washed with methylene chloride and the filtrate was likewise well extracted by shaking with methylene chloride. The combined methylene chloride extracts were dried under reduced pressure and evaporated. The residue was recrystallized from a mixture of methylene chloride and methanol with addition of one dropof pyridine. Yield: 1.04 g., melting point: 212-226 C.

EXAMPLE 3 3-oXo-l4, 15 B-oxido-bufa-4,20 (21 ,22 23 -trienolide (a) 3-ox0-14,1Sa-oxitlo-bufa-BO (21) ,22 (Q3) -trieno-lide (14,15a-oxido scillarenone) 200 mg. of 14-anhydro-scillarenone (3-oxo-bufa-4,14, 20(21),22(23)-tetraenolide) were dissolved in 25 ml. of methylene chloride and combined with a solution of 264 mg. of monoperphthalic acid in ether. The solution was allowed to stand for 2% hours at room temperature, washed with a solution of sodium bicarbonate and water, dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue was filtered over neutral aluminum oxide having the activity degree 11 and eluted with benzene. The eluates were combined and evaporated, the residue was dissolved in a very small amount of hot methanol, the solution was combined, after having cooled, with ether and the crystalline product that had precipitated was isolated. 110 mg. of product melting at 188-l90 C. were obtained.

Infrared spectrum: 1700-1745 cm.- 1650-1670 cm., 1605-1610 CHIS-1, 1525 CIIl. 925 cur- 8l5" 870 cm.

Ultraviolet spectrum: 297 m (5925), 238 m (18700).

(b) 3-oxo-14B,15a-dil1ydroxy-bufa-4,20 (21) ,22 (23)-trienolide (15a-hydroxy-scillarenone) mg. of 14,15a-oxido-scillarenone were dissolved in 1.5 ml. of dioxane; the solution was combined with 0.25 ml. of binormal H 50 and allowed to stand for 43 hours at room temperature, then combined with water and extracted with methylene chloride. The abstract was washed, dried, evaporated and the residue was recrystallized from a small amount of hot methylene chloride. 40 mg. of product melting at 286-288 C. were obtained.

Infrared spectrum: 3500, 3380-3400, 1700-1720, 1640- 1660, 1605-1610, 1530 cmr (c) 3-0xo-14B-hydroxy-15a-methane-sulfonoxy-bufa-4,20 (21 22 (23 -trien0lide (15a-methane-sulfonoxy-scillarenone) mg. of 15u-hydroxy-scillarenone were dissolved in 10 ml. of acetone, the solution was combined with 0.4 ml. of pyridine and 200 mg. of methane-sulfonic acid chloride and stirred for 8 hours at 0 C. The whole was then poured onto ice, extracted with methylene chloride, the extracts were washed successively with Water, dilute hydrochloric acid, water, sodium bicarbonate solution and again water, dried over sodium sulfate and evaporated under reduced pressure at 35 C. 100 mg. of amorphous mesylate were obtained.

Infrared spectrum: 1165 cmf (d) 3-oxo-14,15B-oxido-bufa-4,20 21) ,22 (23 -trienolide (14,1Sfi-oxido-scillarenone) 270 mg. of 1Sa-methane-sulfonoxy-scillarenone werev chromatographed on 12 g. of SiO Elution was effected with benzene and methylene chloride, the eluates were evaporated to dryness and the residue was triturated with ether. Crystals melting at 169-172 C. were obtained.

Infrared spectrum: 1700-1745, 1650-1670, 1605, 1530- 1535, 1110-1120, 850-860, 825 cmr Ultraviolet spectrum: 298 m (7030), 237 rn (23000).

EXAMPLE 4 3B-hydroxy-14,15,8-oxido-bufa-4,20(21),22(23)- trienolide 14,15/3-oxido-scillarenone) mg. of 14,15B-oxido-scillarenone were dissolved in 10 m1. of absolute tetrahydrofurane, the solution was combined at 10 C. with a solution of 873 mg. of

Infrared spectrum: 3420-3460, 1700-1750, 1625, 1535 cmf Ultraviolet spectrum 297 my (4160).

EXAMPLE 5 3-ox0-14,15/3-oxido-bufa-4,20(21),22(23)-trienolide 14, 15 fi-oxido-scillarenone) 200 mg. of crude 3oxo-14;9-hydroxy-15a-bromo-bufa- 4,20(21),22(23)-trienolide (prepared by the reaction of 14-anhydroscillarenone with perchloric acid and N-bromo- References Cited acetamide in dioxane at 15 C. with exclusion of light) UNITED STATES PATENTS were chromatographed on acid aluminum oxide having the activity degree H. Elution was effected with benzene gfii g f f and methylene chloride, the eluates were evaporated to 5 dryness and the residue was triturated with ether. Crys- OTHER REFERENCES tals melting at 169-172" C. were obtained. Fieser et a1: Steroids, pp. 754-756 (1959).

We clam: HENRY A. FRENCH, Primary Examiner 1. 3-oxo-14,15,8-oxido-bufa-4,20(21 ),22 (23 )-trieno1ide. 10 2. 3p hydroxy 14,155 oxido bufa 4,2o 21 ,22 (23)-trienolide. 260-239.55 R, 397.47, 999 

